Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation
| Autor: | Jinlong He, Yin-Jiao Zhao, Xue-Lian Shi, Liu Yao, Yanhong Zhang, Xu Zhang, Bochuan Li, Hui Wang, Zhen Cui, Yi Zhu, Ding Ai |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Epoxide hydrolase 2 endothelium Endothelium mice knockout Blood Pressure bosutinib Pharmacology Endothelial activation Mice Piperidines Bosutinib and Hypertension Downregulation and upregulation Nitriles Internal Medicine medicine Animals Humans Proto-Oncogene Proteins c-abl Mesenteric arteries Cells Cultured Epoxide Hydrolases Aniline Compounds Arachidonic Acid Dose-Response Relationship Drug Chemistry Phenylurea Compounds Original Articles Mice Inbred C57BL Vasodilation medicine.anatomical_structure Eicosanoid ComputingMethodologies_DOCUMENTANDTEXTPROCESSING Quinolines incidence Endothelium Vascular Bosutinib Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Hypertension (Dallas, Tex. : 1979) |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.121.17548 |
| Popis: | Supplemental Digital Content is available in the text. Endothelial cells play a critical role in maintaining homeostasis of vascular function, and endothelial activation is involved in the initial step of atherogenesis. Previously, we reported that Abl kinase mediates shear stress–induced endothelial activation. Bosutinib, a dual inhibitor of Src and Abl kinases, exerts an atheroprotective effect; however, recent studies have demonstrated an increase in the incidence of side effects associated with bosutinib, including increased arterial blood pressure (BP). To understand the effects of bosutinib on BP regulation and the mechanistic basis for novel treatment strategies against vascular dysfunction, we generated a line of mice conditionally lacking c-Abl in endothelial cells (endothelial cell-AblKO). Knockout mice and their wild-type littermates (Ablf/f) were orally administered a clinical dose of bosutinib, and their BP was monitored. Bosutinib treatment increased BP in both endothelial cell-AblKO and Ablf/f mice. Furthermore, acetylcholine-evoked endothelium-dependent relaxation of the mesenteric arteries was impaired by bosutinib treatment. RNA sequencing of mesenteric arteries revealed that the CYP (cytochrome P450)-dependent metabolic pathway was involved in regulating BP after bosutinib treatment. Additionally, bosutinib treatment led to an upregulation of soluble epoxide hydrolase in the arteries and a lower plasma content of eicosanoid metabolites in the CYP pathway in mice. Treatment with 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea, a soluble epoxide hydrolase inhibitor, reversed the bosutinib-induced changes to the eicosanoid metabolite profile, endothelium-dependent vasorelaxation, and BP. Thus, the present study demonstrates that upregulation of soluble epoxide hydrolase mediates bosutinib-induced elevation of BP, independent of c-Abl. The addition of soluble epoxide hydrolase inhibitor in patients treated with bosutinib may aid in preventing vascular side effects. |
| Databáze: | OpenAIRE |
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